RADIOLOGICAL USE OF FAST PROTONS

ROBERT R. WILSON

Research Laboratory of Physics, Harvard University

Cambridge, Massachusetts

Except for electrons, the particles which have been accelerated to high energies by machines such as cyclotrons or Van de Graaff generators have not been directly used therapeutically. Rather, the neutrons, gamma rays, or artificial radioactivities produced in various reactions of the primary particles have been applied to medical problems. This has, in large part, been due to the very short penetration in tissue of protons, deuterons, and alpha particles from present accelerators. Higher-energy machines are now under construction, however, and the ions from them will in general be energetic enough to have a range in tissue comparable to body dimensions. It must have occurred to many people that the particles themselves now become of considerable therapeutic interest. The object of this paper is to acquaint medical and biological workers with some of the physical properties and possibilities of such rays.

To be as simple as possible, let us consider only high-energy protons: later we can generalize to other particles . The accelerators now being constructed or planned will yield protons of energies above 125 Mev (million electron volts) and perhaps as high as 400 Mev. The range of a 125 Mev proton in tissue is 12 cm., while that of a 200 Mev proton is 27 cm. It is clear that such protons can penetrate to any part of the hody.

The proton proceeds through the tissue in very nearly a straight line, and the tissue is ionized at the expense of the energy of the proton until the proton is stopped. The dosage is proportional to the ionization per centimeter of path, or specific ionization, and this varies almost inversely with the energy of the proton. Thus the specific ionization or dose is many times less where the proton enters the tissue at high energy than it is in the last centimeter of the path where the ion is brought to rest.

These properties make it possible to irradiate intensely a strictly localized region within the body, with but little skin dose. It will be easy to produce well collimated narrow beams of fast protons, and since the range of the beam is easily controllable, precision exposure of well defined small volumes within the body will soon be feasible.

Let us examine the properties of fast protons some what more quantitatively. Perhaps the most important biological quantity is the specific ionization, or number of ions per centimeter of track. This
quantity is not difficult to calculate. The results of such calculations are shown in Figure 1, where the range of protons in tissue is plotted for protons of various energies. In the same figure, the specific ionization is plotted as a function of the range in tissue. For purposes of calculation, tissue has been assumed to have the molecular formula (1): C0.5 H8 O3.8 N0.14, and to be of unit density, i .e., 15 percent protein and 85 percent water. The calculations can be easily extended to other materials and densities.(2) The accuracy is perhaps 5 percent. However, exact values for varions tissues can be quickly measured as soon as the fast protons are available.

Figure 1 shows, for example, that if we want to expose a region located 10cm. below the nearest surface, it will be necessary to have protons of 115 Mev. If a depth of 15 cm. were required, then 140 Mev protons would be needed. The specific ionization curve needs a little interpretation. If we interpret the abscissae as the residual range, then there should be little difficulty in visualizing the specific ionization at various depths within the body. As a particular example, let us consider 140 Mev protons. In Figure 2, the dotted line is a depth-dose curve obtained by plotting the specific ionization taken from curve II of Figure 1 against the depth of proton in the tissue. Thus, at the surface, the residual range is 15 cm., and curve II of Figure 1 shows that the specific ionization for a proton of 15 cm. range is 0.l5 million ion pairs per centimeter. This point has been adjusted to 100 percent in Figure 2. When the proton has proceeded into the tissue 7 cm., its residual range is 8 cm. and the ionization of a proton of 8 cm. range is 0.2 million ion pairs per centimeter or 133 percent of the surface dose. The rest of the curve can be obtained in the same way, and we see that the curve rises sharply in the last few centimeters. The average ionization over the last centimeter is about six times that at the surface. In the final half centimeter of a particular proton track, the average dose is sixteen times the skin dose. The full curve is perhaps more realistic, however, and it will be explained later.

It is well known (2) that the biological damage depends not only on the number of ions produced in a cell, but also upon the density of ionization. Thus the biological effccts near the end of the range will be considerably enhanced due to greater specific ionization, the degree of enhancement depending critically upon the type of cell irradiated.

At this time we might inquire about the current of protons required for an irrad iation. I shall use the roentgen equivalent dose, as it particularly is amenable to calculation for this application. One roentgen equivalent dose (r.e.d.) of protons will have been received at a certain point in the tissue when 83 ergs of energy have been absorbed per gram of tissue. In the last centimeter of range a proton loses 30.1 Mev (energy of a proton of 1.0 cm. range; see curve I of Figure 1). Since 1 Mev is equal to 1.6 millionths of an erg, each proton loses 48 millionths of an erg in the last centimeter. Hence, to produce 1 r.e.d. averaged over the last centimeter of depth requires 83/48 X 10 6 = 1.72 million protons per square centimeter. To produce 1,000 r.e.d. will require 1.72 billion protons per square centimeter. This corresponds to a current of 2.75 X 10 -10 amp./cm.2 of protons for a one-second exposure or 4.6 X 10 -13 amp./cm.2 for a ten-minute exposure.(3) The machines now under construction should have little difficulty in producing such currents. In fact, it is expected that they will yield currents millions of times as great. It will be simple to collimate proton beams to less than 1.0 mm. diameter or to expand them to cover any area uniformly.

Let us now become a little more technical and consider secondary effects. First, the energy loss of the proton is a statistical effect due essentially to the production of ions along its path; hence, not all protons of the same energy will stop at the same distance beneath the skin. This effect is called range straggling and is easy to calculate. The results of such calculations can be summarized by saying that the longitudinal width in which most protons come to rest is about 1 percent of the initial range.(4) The effect of this on the depth dose curve is qualitatively shown in Figure 2. As a result of straggling, the full curve obtains instead of the dotted one.

A second effect is due to the many small angle scatterings of the proton as it passes the nuclei of the atoms of the tissue. This is called multiple scattering, and its effect is to spread the end of the beam out transversely. It is also easy to calculate, and it turns out that the transverse width which an infinitely narrow starting beam would have at the end of its range is about 5 percent of the initial range.(5) Both effects are small, but they do indicate the limitations of precision available.

A third effect is that due to the nuclear absorption and scattering of the protons. The exact behavior of protons in nuclear reactions at such high energies as considered here must be determined by experiments to be carried out in the future. Present experiments using high-energy neutrons give good estimates of the radii of most nuclei (3). Probably whenever a fast proton hits the nucleus it will he captured and its energy will appear in several slower protons, alpha particles, or neutrons. In any case, the probability of a proton impinging on a nucleus after traveling 10 cm. in tissue will be about 25 percent. The effect tends to decrease the specific ionization at the end of the range by 15 to 30 percent. Inasmuch as the specific ionization is several times greater at the end of the range than it is at the beginning, this will not be serious.

A similar effect is that due to elastic scattering of the protons by nuclei. The probability of this type of scattering is essentially the same as that of absorption. In this case, however, the proton is not stopped but continues at the same energy but in a different direction. The effect, then, is to diffuse about 20 to 40 percent of the beam. For fairly broad beams this would not be noticeable because such scattering will be predominantly forward.

The above should be the principal effects, and we see that our original picture of a proton beam proceeding without spreading until it is stopped at highspecific ionization in the tissue is only slightly modified. It will be possible to treat a volume as small as 1.0 c.c. anywhere in the body and to give that volume several times the dose of any of the neighboring tissue. The exact behavior of protons of the energy considered here will become known only when such protons are available for experiment.

In treating large tumors, for example, one will want to cover the whole volume with the very high ionization density which obtains over the last few millimeters. This can easily be accomplished by interposing a rotating wheel of variable thickness, corresponding to the tumor thickness, between the source and the patient.

The exposure can be monitored precisely simply by placing a shallow ionization chamber between source and patient. Absolute determinations of the dosage can be determined by measuring ionization currents in gases of the elements of tissue or in a gas which mocks up the molecular formula of tissue. What makes the problem of dosage measurement so simple is the absence of the wall effects encountered in x-ray or neutron exposure measurements. This is because the high-energy proton produces its secondary electrons at such low energy that their range is essentially zero.

The above results are easily generalized to other particles. Range and specific ionization of deuterons or alpha particles can be determined from Figure 1 for protons. If the proton energy ordinates are multiplied by two, as well as the range, curve 1 then holds for deuterons. Thus a 200 Mev deuteron has 16 cm. range. The specific ionization remains the same, however, and a deuteron of 16 cm. range makes 0.14 X 10 (6) ion pairs per cm. For alpha particles both ordinates are multiplied by four, but the range is left unchanged. Thus a 400 Mev alpha particle has a range of only 8 cm., but its specific ionization is 0.8 X 10(4), four times as great as for a proton of the same range. The intense specific ionization of alpha particles, when considered in the light of Zirkle 's results, will probably make them the most desirable therapeutically when such large alpha particle energies are attained. For a given range, the straggling and the angular spread of alpha particles will be one-half as much as for protons. Heavier nuclei, such as very energetic carbon atoms, may eventually become therapeutically practical.

One naturally asks what are the advantages of fast protons over high - energy electrons such as those from a betatron (4). This question can be answered only by medical workers, and the answers will probably be different for different kinds and sizes of tumors. Certainly the differences between fast electrons and protons are only quantitative. The specifice ionization for protons is much greater, and the concentration of ionization in a given volume is also greater because the straggling and spreading of electrons is worse. On the other hand, electrons of sufficient energy can be produced by more modest equipment.

Finally, I would like to emphasize the danger which will be lurking near the proposed high-energy machines. We have seen that a current density of a few times 10 -10 amp./cm.(2) for one second could have lethal effects. The particles can penetrate the metal walls of the machines, and if less than one billionth of the proposed currents of about one microampere is scattered in the wrong direction, then workers may be in danger. This becomes particularly apparent when one considers that the range in air of a 150 Mev proton is about 150 meters. On the other hand, the range of such a proton in lead is only a few inches, and with thoughtful precaution accidents can be averted.

(1) Accepted for publication in July 1946.
(2) The range of a proton in air in meters is given by the convenient formula R = (E/9.29)(1,8) where the energy is expressed in Mev. The range in tissue is 1.11 X 10-3 times the range in air. The stopping power of other substances may be found in Livingston and Bethe: Rev. Mod. Physics 9:246, 1937. The physical calculations of this paper will be submitted to the Physical Review for publication.
(3) More generally the r.e.d. at a point x cm. below the surface is givcn approximately by the formula
r.e.d. = 4.8 X l0 (10) jt/(R -X)0.411
where R is the total range of the proton in tissue in cm., j the cuurent density or protons in :amperes/cm(2)., and t the exposure time in seconds. The formula is not accurate in the last millimeters of range.
(4) The protons come to rest so that the distribution of their end-points is given by P(x)dx = R/α√π bar e- (R -x)2/R(2)α(2) dx, where x is the distance below the surface, and α is given byα = 7.1/E01/2 (NZ z(2)R/E0)-0.055 where N is the atoms per cm.3, Z is the atomic number, z is the ion charge number, E0 is the rest energy of the ion in MeV, and R is the range in cm.
(5) The transverse distribution of the end-points of the protons is given by
P(y)dy = R/ß√πbar e y2/R(2)ß(2) dy
where y is the distance from the average end of the range measured perpendicular to the initial direction of the beam and ß is given by
ß = 12 (Z/E0) 1/2 (NRZ2(1)/E0) -0.055
The numerical constant should he determined more accurately by experiment.

NEUTRONS AGAINST CANCER: FERMILAB CANCER THERAPY FACILITY

INTRODUCTION
Modern medicine employs three primary forms of cancer treatments: surgery, chemotherapy (medication), and radiation therapy. The location, type, and size of the cancer determine the treatment method(s). In many cases, varying combinations of the three types of treatment are used.

Preparing patient for treatment at Fermilab

A new type of radiation therapy, called neutron therapy, is being offered as an experimental program at Fermilab. To conduct this research, the Laboratory has established a Cancer Therapy Facility (CTF).

This research program, together with three other centers in the United States, tests the effectiveness of neutron beams by comparing them with conventional radiation in the management of certain tumors.

RADIATION THERAPY
In radiation therapy, penetrating rays are used to treat cancerous tumors. The rays may come from x-ray machines, from radioactive substances, or from accelerators (machines that speed up subatomic particles).

Basically, radiation therapy destroys cells. The treatment is designed to destroy as many cancerous cells as possible, while doing the least harm to normal cells. During therapy both cancerous and normal cells die. However, the healing mechanisms of the body replace the dead normal cells.

The success of a treatment is measured by the extent of tumor eradication versus the damage to the surrounding normal tissues. A patient's response to treatment depends on the nature and extent of the tumor.

CTF aide positions patient in treatment room

NEUTRON THERAPY
The Fermilab CTF opened in September 1976. It evolved from studies on laboratory animals and patients who have undergone neutron therapy here, elsewhere in the United States, and across the world.

Neutrons are particles found in the heart of every atom -the nucleus. Neutrons act on human tissues much like x-rays. These radiations destroy cells by changing their genetic character and thus creating offspring that cannot survive. There are, however, some cells in the tumor that are oxygen deficient (hypoxic cells) and these are known to be resistant to the effects of x-rays.

These cells are believed to be responsible for the reappearance of the tumor after conventional (x-ray) therapy. Hypoxic cells are not "resistant" to fast neutrons. Hence, the use of this beam will hopefully increase tumor control. This, however, must be scientifically proven.

Cancers treated in the program are those in which conventional therapy is unlikely to provide control. Possibilities are that neutron results will be better or similar to conventional radiation. Patients who participate help the advance of medical knowledge by establishing the effectiveness of this new therapy.

CTF patient reception area

Those who have offered to participate in these studies may at any time choose not to be a part of this project or may withdraw before completing neutron treatments.

These patients may then continue their treatment with conventional therapy. An institutional review board (IRB) reviews proposed studies and decides if potential benefits exceed risks for the patients. In addition, the IRB assures adequate protection of the rights and privacy of patients. Fermilab's IRB comprises three out-of-town radiotherapists, a medical physician, an attorney, two medical oncologists, a social worker, an oncollogical nurse, and a professor of theology.

The cancers treated are described in study protocols designed by a national group of radiation therapists under the auspices of the National Cancer Institute. Patients are referred by a radiation therapist to the study only if they have been identified as having a suitable cancer which will benefit from fast neutron therapy. This further assures that the neutron treatment is in the best interest of the patient.

Dr. I. Rosenberg, medical physicist, adjusts CTF controls

Certain tumors of the mouth and upper respiratory passages, advanced cancers of the cervix, prostate, bladder, and some brain cancers are being treated at U.S. neutron centers. In addition, at Fermilab some cancers of the lung and pancreas as well as certain bone and soft tissue malignancies are irradiated in conjunction with surgery and chemotherapy.

Treatment with neutrons is delivered in a sitting or standing position. Special devices are used to correct the position and immobilize patients. Treatments including set-up and irradiation require twenty to thirty minutes depending on the region of the body involved. During treatment the patient is observed by closed circuit television and communication is maintained by an intercom system. Generally, treatment is given one to four times a week and may last from three to seven weeks.

D. Zimmer checks patient x-rays

After the course of neutron therapy at Fermilab is completed, the patient returns to his referring physician and radiotherapist for evaluation and follow up. Patients are also asked to report periodically at Fermilab for check-ups. These follow-ups at Fermilab are done without charge.

As each patient contributes to the research, all data are recorded and sent for analysis by modern computer techniques. Personal privacy is assured. Patients' identities are unknown to statistician and research workers evaluating results. Physicians and allied scientists participating in this study across this country have access to results and are able to get valuable information from the study.

CTF entrance at Linear Accelerator

TREATMENT EFFECTS
The effects of neutron treatment, like all radiation therapy, depend on the part of the body being treated. Effects on normal tissues are minimized by careful planning and by dividing the total radiation dose into many fractions. Some side effects may be anticipated. Many of these side effects are transient and tissue recovery occurs with time.

FACILITIES
Fermilab operates the most powerful particle accelerator in the world. It was built for high energy physics research. The Cancer Therapy Facility is possible at Fermilab because injector equipment in the linear accelerator is used for only about 30% of the time to supply protons for physics research. During the remaining time, the injector system is available for use by the CTF for cancer treatment, typically seven out of every ten seconds.

To create the CTF, a small area parallel to the linear accelerator was remodeled. After a year of initial dosimetry and radiobiology studies, patient therapy was started in September, 1976. It contains the heavily-shielded treatment room and other rooms for reception, examination, and controls. The facility is easily accessible to patients through a nearby outside ground level door.

The treatment room has two levels. An upper one is designed for access and contains x-ray diagnostic equipment used to confirm that the patient is properly placed with respect to the X beam. Then the platform is lowered and the patient is placed in the neutron beam at the treatment point. This point at the lower level is defined by four lasers.

Neutrons are produced in all directions when protons diverted from the linear accelerator strike a beryllium target. An absorbing wall with appropriately-tapered holes is placed between the neutron source and the patient. The proper hole assures that only the part of the body that the physician wants to treat will be actually irradiated. The patient is precisely positioned in the neutron beam with the help of the beam lights (lasers).

Neutron beam therapy is suitable for patients who are ambulatory. Patients walk into the treatment room and must be able to hold their treatment position for the duration of therapy. While the Cancer Therapy Facility has a full medical and nursing staff, there are no inpatient beds. In case of an emergency, a patient at Fermilab is taken to a nearby hospital for immediate care. If inpatient care is needed, the patients are referred back to their original hospitals and the therapy is interrupted or they may come to Fermilab in an ambulance.

COST
No charge is made to patients for the use of the beam or the facilities at Fermilab. Patients have to arrange for their own transport. Sometimes the Illinois Cancer Council and volunteers of the American Cancer Society help in patient transport.

FUNDING
Beginning June 13, 1975 the National Cancer Institute (U. S. Dept. of Health, Education, and Welfare) granted $816,000 for three-year operating funds for the CTF. After an independent on-site review, NCI awarded a second three-year grant effective August 1, 1977 of $2,186,953, for operating expenses. The Illinois Division of the American Cancer Society has made two research and instrumentation grants totalling slightly over $35,000 to finance dosimetry equipment, beam time, travel and other expenses.

Through the efforts of the medical profession in the Chicago area, led by Dr. Samuel Taylor III, private funds were contributed for building modifications to accommodate the new facility and for some equipment. The Field Foundation donated $50,000; the Joyce Foundation $50,000; the A. B. Dick Company $50,000; the Chicago Trust (through Harry L. and Elizabeth Marshall, Dr. Adolph Gehrmann, and the William Allen Pusey Fund) $50,000; Elliott Donnelley $10,000; Robert R. McCormick Charitable Trust $50,000; Amoco Foundation $10,000; Metropolitan Association of Radiation Therapists $106. Private individuals have donated close to $5,000.

HISTORY
Robert R. Wilson, Fermilab Director from its founding in 1968 until July, 1978, proposed as early as 1947 that proton accelerators could be used to treat cancer victims. Leading oncologists (physicians specializing in cancer treatment) and radiotherapists in the Chicago area working with Dr. Wilson and other Fermilab staff members, over a period of three years developed the ideas and plans that are a reality at Fermilab. The opening of the Fermilab Cancer Therapy Facility gave the midwest medical community its first fast neutron radiation research facility.

Since 1961, patients have been irradiated with neutron beams at the Hammersmith Hospital in London, the M. D. Anderson Hospital and Tumor Institute in Houston, the Naval Research Laboratory, Washington, D. C., and the Washington University in Seattle. In 1969, the Hammersmith Hospital began to see impressive local tumor control with the use of neutron irradiation.

Fermilab's CTF operating group was established in mid-1975. Dr. Lionel Cohen, head of radiation therapy at Michael Reese Hospital, Chicago, assumed the position of head, on a part-time basis.

Measurement of the neutron beam characteristics began in October and consisted mainly of measurements to determine dose distributions. These continued until early 1976, when the facility was shut down to permit replacement of the temporary shielding with permanent shielding. Pilot studies were begun September 7, 1976, with a tongue cancer patient.

National participation means that patient treatment results from Fermilab will be combined with comparable data being compiled at the other national treatment centers: M. D. Anderson Hospital and Tumor Institute, Houston, Texas, and the Naval Research Laboratory, Washington, D. C.

CANCER THERAPY FACILITY AT FERMILAB FINDS ITS PLACE IN MODERN HEALTH CARE

Dr. Frank R. Hendrickson (left) and Brian Pientak, radiation
therapy
technologist,
in the Cancer Therapy Facility at
Fermilab.
They are in the
shielded
room in which
patients
are exposed to neutrons.
The patients sit in
the chair
between them. Just above
Hendrickson's left hand is a
laser device that
technologists use to precisely align a
patient with the neutron source

Neutron therapy is becoming an important new technique for bringing certain types of cancer under control. Dr. Frank R. Hendrickson, associate director of the Cancer Therapy Facility (CTF) at Fermilab, told science writers attending a press conference at the joint annual meeting in Chicago of the American Physical Society and the American Association of Physics Teachers.

Also professor and chairman of the Department of Therapeutic Radiology at Rush-Presbyterian-St. Luke's Medical Center in Chicago, Dr. Hendrickson said that for certain types of cancer, treatment with neutrons appears to be promising. However, he cautioned the writers about becoming overzealous. The Fermilab facility has been running only since October 1976, not long enough for substantial data to have been accumulated on the long-term effects of neutron therapy on patients, he explained.

Yet, he was optimistic and enthusiastic about neutron therapy. Even though it appears to be effective with certain types of cancer, the results should be thought of as an improvement over standard modes of treatment, not regarded as a breakthrough, he said.

Since the Fermilab CTF opened, more than 600 patients have been exposed to neutrons. The types of cancers that have been treated include those of the salivary glands, advanced head and neck cancers and malignant tumors of the pancreas and brain. These cancers have a tendency to remain localized and less often spread to other parts of the body, thus making them good candidates for neutron therapy. Some of the patients had cancers that were too large to be removed by surgery, or just didn't respond to the standard treatment modes. These include radiation, chemotherapy and surgery.

The average patient at Fermilab gets about six or seven neutron treatments, but range from 2-20 said Hendrickson at the press conference. Some of the treatments may be as infrequent as one each week, and as frequent as three a week. Each exposure lasts only a few minutes.

"In no situation has the treatment been worse for the patient than would have been the standard treatment," said Hendrickson. "Our result in every case has been at least as good."

The facility at Fermilab is capable of treating up to about 50 patients a week, he said. At the present time, about half that number are being seen.

He reminded the science writers that "cancer is the most curable dreaded disease we have. The cure rate is about 50 percent. If the cancer is caught in its early stages, that cure could be as high as 90 percent." It is the leading cause of death in people under 55, he added.

Indeed, therapy with neutrons appears to be an important missing link in the spectrum of treatments available, according to Dr. Hendrickson. Just before his press conference, he addressed the annual meeting on "The Physical and Biological Basis for Neutron Treatment."

He showed color slides of some patients with malignant tumor growths of the ear, side of the face and soft palate inside the mouth. After neutron treatment, their recovery was remarkable. From the color slides showing the patients following therapy, only their physician would have known an ugly tumor had once ever deformed their features. It was dramatic visual evidence of the powerful role neutron therapy is gaining in modern health care.

It wasn't always that way. In the 1940's, some work was done with neutron therapy, Dr. Hendrickson told his audience at the meeting. Unfortunately, the mechanism of action and biology of the treatment was not fully and correctly understood. Consequently, the results were less than desirable. So interest in using fast neutrons waned.

In the late 1960s and early 1970s, an attempt at using neutrons was started at Hammersmith Hospital in London. With improved understanding and more sophisticated equipment, some of the results were gratifying, he said. From this second cautious beginning, interest spurted and spread to this country and to others throughout the world. In the past 10 years, 4,000 patients have been treated at neutron therapy facilities, most of them in the past few years.

"To date, clinical research has not progressed sufficiently to reach firm conclusions, but the general direction of the observation has paralleled that of the initial work in England," said Dr. Hendrickson at the meeting. "Within the next several years, sufficient followup will have been achieved to reach firmer conclusions."

He also said, "The potential for improvement in the management of cancer patients with radiation therapy has come about from the intense cooperative interaction among the physical sciences, biological sciences and medical sciences.

Without this high degree of precision and indepth understanding of the absorption of heavy particles in various physical materials, the whole program could not have begun."

He concluded his remarks at the annual meeting by saying, "The medical sciences have been able to combine physical and biological research data into clinical research programs that compare the best of the standard treatments with these new frontiers."

And at the press conference, Dr. Jacques Ovadia, chairman of the Medical Physics Department at Michael Reese Medical Center in Chicago and also a speaker at the annual meeting, gave his overview. He said, "Neutron therapy has come of age."

Commercial equipment is available now and hospitals are capable of running the units reliably, he continued. "We are not giving anything away in terms of good patient care by using neutrons," Dr. Ovadia also said.

Dr. Hendrickson added that it will probably be three or four years before patients will be treated with these units.

FERMILAB: ITS ROLE IN PROTON THERAPY DEVELOPMENT IN U.S.

Robert Wilson, the creator of
proton therapy and the
founder of Fermilab

Fermilab from the air

The world's highest energy accelerator at Fermilab

Robert Wilson founded Fermilab and led it through its first decade. He maintained his long-standing interest in proton therapy, and in the early 1970's, he and some of his colleagues proposed to use the Fermilab linear accelerator for therapy when it was not in use as an injector. But, the ability to make use of the localized dose of protons depends on knowing the location of the tumor. The technology to perform this localization was not fully developed at that time, and the physicians collaborating with Fermilab urged them to produce neutrons with the proton beam and to perform therapy with neutrons. Neutrons are somewhat more efficient than protons or electrons at killing cells, but do not have the great advantages of protons in localizing the dose. The Fermilab Neutron Therapy Facility has been in operation for more than ten years and has treated more than 1,600 patients.

In the intervening years, proton therapy has proceeded at Harvard, and CAT scanning and MRl have come to fruition. With their use, it is possible to take full advantage ofthe tight control of the irradiated site that is possible with protons. It is now advantageous to build an accelerator and facility specifically for the treatment of disease with proton beams in a hospital setting.

Robert Wilson Hall, the laboratory building that is
the focus of Fermilab

In January 1985, a group interested in studying the design of potential proton accelerators, facilities, and clinical trials met at Fermilab in Batavia, Illinois for the first in a series of meetings. In these meetings, the group, which came to call itself the Proton Therapy Cooperative Group (PTCOG), proposed and discussed a variety of machine designs and beamdelivery systems. One outgrowth of the PTCOG meetings has been an agreement between Loma Linda University and Fermilab, whereby Fermilab will design and fabricate a 70 to 250 MeV proton synchrotron and assist in the design and procurement of a beam transport and delivery system for installation at Loma Linda University Medical Center.

Fermilab is owned by the United States Department of Energy and operated by Universities Research Association, Inc.

Source: Proton Therapy and the Control of Cancer, Loma Linda University Medical Center, 1989

FERMILAB BUILDS PROTON ACCELERATOR TO TREAT CANCER

The U.S. Department of Energy's Fermi National Accelerator Laboratory at Batavia has announced the first successful operation of a small proton accelerator to treat rare cancers.

It was designed and built at Fermilab for Loma Linda University Medical Center in California, where it will be used to treat cancer and other diseases by focusing a beam of protons to eradicate diseased cells.

Fermilab employees work on the new proton therapy accelerator. The new synchotron will be used for the treatment of cancer and other diseases. Designed and built at Fermilab, it will be disassembled and moved to Loma Linda University Medical Center in California. Fermilab will continue to operate its neutron therapy facility for cancer treatment.

The first operation is an important step in a 1986 agreement between the medical center and Fermilab, according to Fermi officials.

Under the agreement the accelerator will be disassembled and moved to Loma Linda during the summer of 1989 when the critical facilities for the treatment of patients are ready. In the interim Fermilab will continue start-up procedures although it will not be used to treat patients, Fermilab
will continue accepting patients in its neutron therapy facility.

The proton therapy accelerator is 20 feet in diameter -- the world's smallest proton synchrotron -- and will deliver a variable energy of 70 to 250 MeV (million electron volts). In comparison, the Fermilab Tevatron -- the world's largest -- is 4 miles in circumference and delivers energies of approximately l trillion electron volts.

Use of protons for cancer therapy was first proposed by Robert Wilson, the first Fermilab director, immediately after World War II while he was at Harvard University. Pioneering work has been carried out for many years at the Harvard Cyclotron Laboratory built by Wilson at the Lawrence Berkeley Laboratory at the University of California in Berkeley, and at laboratories in Sweden, the Soviet Union and recently in Japan. All of this work has made use of accelerations originally built for scientific research and later adapted for cancer therapy.

The work has proved that proton therapy has significant advantages over other methods of cancer treatment such as X-rays or neutrons. The greatest advantage is that the proton beam limits the radiation dose to the disease site, reducing the side effects of treatment while killing disease cells.

The new accelerator built at Fermilab is the first designed specifically for therapy. It has several special features, such as precise energy control and long beam spill that are included to make therapy easier and more efficient.

The facility at Loma Linda will have four treatment rooms, three with gantries to bring the beam to the disease site from any desired angle and one specialized room for treatment of the head and neck. It will be possible to treat many more patients than has been possible in the past. New treatment aids planning methods are being developed in the center.

NEW PROTON ACCELERATOR DRAWS BEAD ON CANCER CELLS

Using technology they developed to hunt for quarks and other exotic natural particles, Fermilab scientists have produced a unique roomsize proton accelerator that may be able to kill cancer cells better than any other type of radiation.

The compact accelerator is designed to do something that other radiation devices cannot -- destroy diseased cells while leaving healthy cells basically ulnharmed.

This proton therapy accelerator at Fermilab near Batavia will be shipped to Loma Linda
University Medical Center in California for use in a revolutionary new treatment of cancer patients

"It's a revolutionary treatment," said Philip Livdahl, former Fermilab deputy director and now project manager for Loma Linda University Medical Center in Loma Linda, Calif., where the new machine is expected to begin work this summer.

"When this technology reaches its full potential, I think it will replace X-rays and other forms of radiation for cancer therapy."

X-rays and gamma rays,which are now used to destroy cancerous tissue, pass through the body, causing damage along the entire length of their paths. Radiation kills cells by destroying genetic machinery.

Because these radiation beams destroy healthy tissue before reaching a tumor, physicians often have to reduce the destructive dose of the beams, which may reduce the ability of the radiation to kill the cancer.

A proton beam, on the other hand, overcomes this drawback by delivering a much higher radiation dose to the tumor than it does to surrounding tissue.

The proton beam can be focused to release its destructive radiation at any target within the body, such as a tumor, without destroying normal cells along the route of the beam. Protons are subatomic particles found in the nuclei of atoms.

A proton beam enters the body at an energy low enough not to damage tissue. The beam then slows down and stops at a point that can be exactly determined.

When the beam stops at its target, it is absorbed by atoms there, releasing nine times more energy than it had when it entered the body. It is this energy released at the target that destroys the tumor.

Combined with new imaging devices that produce three-dimensional pictures of the interior of the body, including precisely outlining the boundary between cancerous and healthy tissue, a proton beam can be used to eradicate a cancer with surgical accuracy, said Dr. James Slater, a Loma Linda cancer specialist.

"In order for cancer radiation therapy to advance we needed to improve our ability to focus a beam inside the body. The proton accelerator does that," he said. "It's a superior tool that's going to produce a major improvement in cancer therapy."

The accelerator, which is undergoing shakedown tests at Fermilab, is one of the promising spinoffs from high-energy physics research at the center, located near Batavia. A product of the laboratory's program to find practical uses for its specialized technology, the machine is the first proton therapy accelerator designed exclusively for patient treatment.

"We're all excited about the physics going on at Fermilab, but we appreciate the opportunity to do something real with what we've learned over the years to help mankind," said Livdahl.

Doctors have known that proton beams might be a powerful weapon against cancer, but the technology to produce flexible beams in adequate amounts has not been available.

Patients had to travel to physics research facilities where particle accelerators could be used for cancer therapy when they were not occupied smashing atoms. These beams, furthermore, were not flexible, so few types of cancer could be treated.

As a result, only a small number of patients have been treated with proton beams-about 6,000 over the last 15 years. But the results have been so good that physicians expect the technique will result in more cures.

One of the most dramatic improvements has been achieved with an eye cancer known as ocular melanoma, a tumor that grows on the inside of the eye. Standard therapy, which consisted of removing the eye, produced dismal results, with the cancer reappearing at some other site in the body in 65 percent of patients.

Since physicians started treating this cancer with a proton beam produced by an old atom smasher at Harvard University, however, they have been able to eliminate the cancer in 96 percent of cases without having to remove the eye, said Livdahl.

Furthermore, there is no loss of vision in 75 percent of the treated eyes, he said.

In an effort to break the logjam over the limited availability of proton beams, Loma Linda officials in 1986 asked Fermilab physicists if they could build an accelerator to produce protons for cancer therapy. Loma Linda is building a new $40 million proton beam radiation facility.

OFF THE BEAM?

BATAVIA, Ill. -- It is a vision of the future that medical scientists have had for more than 40 years:

Inside a space-age hospital room, a team of doctors activate an atomic accelerator. When the whirling protons reach full speed, tbe doctors fire them through a device that looks like a giant Ferris wheel and into the body of a cancer patient. In a few seconds, the proton beam kills cells in a cancerous tumor, leaving nearby healthy cells untouched.

Now, this vision is no longer so far away. Last month, scientists at the Fermi National Accelerator Laboratory here unveiled the first proton beam accelerator built for hospital use. When the machine is ready for operation next year at Loma Linda University Medical Center near Los Angeles, many believe it will prove itself a major breakthrough in the war on cancer.

Others, however, think the proton accelerator is a white elephant. They complain that its untested medical benefits and enormous price make it the ultimate example of medical technology run amok. Some doctors say proton therapy will prove useless in the treatment of most cancers.

Most Expensive Ever
It is unquestionably the most expensive piece of medical equipment ever built. The cost -- $40 million, including the special building needed to house the machine -- dwarfs the cost of the next most expensive medical device: the Positron Emitting Tomography scanner, which shows metabolic activity within the brain and can cost about $5 million.

"It's really stratospheric" for a medicalcal technology, says Peter Ogle, the editor of the trade magazine Diagnostic Imaging. Adds James Slater, the Loma Linda physician directing the project: "It's the most complicated machine ever used in a hospital setting by far." Loma Linda's expectations
that the device will eventually treat between 1,000 and 2,000 patients annually "assume the machine stays up and running," Dr. Slater says.

Last year, the project nearly fell victim to federal budget cutters, when the Office of Management and Budget concluded it was a pork barrel project. The agency recommended that $11.5 million in federal funds pledged to the beam be withheld, but Congress ignored the advice.

At this stage, Loma Linda officals say they can't even begin to guess what patients will be charged for treatment on the machine.

Selling Points
Nevertheless, the device does have wide support. Proton therapy for cancer is believed to have a number of advantages over chemotherapy, conventional radiation and surgery.

X-rays, for instance, are harder to tame than protons. Not only do X-rays have a tendency to scatter - hitting good tissue around a malignancy - but they also strike, and damage, healthy tissue behind a tumor. In that respect they are like subatomic runaway trains.

Nausea, pain, new cancer and even death are sometimes side effects of conventional radiotherapy. To avoid complications, doctors often lower radiation dosages to spare healthy tissue. But that can allow malignant cells to live and persist in their destructive course.

Protons, however, are more like crack combat troops. The subatomic particles strictly obey doctors' commands. Found in the nuclei of atoms, protons go precisely where doctors want them to and no farther. So while a tumor is being bombarded to death by protons, surrounding. normal tissue isn't.

Protons were first suggested as a potential cancer therapy in 1946 by Robert Rathbun Wilson, who established the Fermi National Accelerator Laboratory. But it wasn't until the 1970's that patients were first exposed to protons in physics labs at Harvard University, the University of California at Berkley, at Fermi and at several institutions abroad.

Moonlighting Machinery
In physics labs cluttered with cable and oscilloscopes, physicists have seen some spectacular results using physics research machines moonlighting to treat cancer patients.

At Harvard, where 174 patients with malignant tumors at the base of the brain have been treated, the therapy has had an 85% cure rate, compared with a 35% cure rate for conventional therapies. (Patients in remission or cancer-free for five years are considered cured.)

Loma Linda, a Seventh Day Adventist institution, had been intrigued with the proton accelerator since the early 1970's. But the hospital didn't do much more than think about it because the needed computing technology and magnetic resonance imaging were either prohibitively expensive or nonexistent. Magnetic resonance imaging, or MRl, is a way of seeing internal organs without radiation. Perfected in the 1980's, it sets up a magnetic field. Different body tissues absorb varying levels of magnetism. Through computer enhancement, an MRI device converts those differences into detailed images of the body.

Then, in 1987, after the study group decided that a hospital accelerator could be built for about $20 million, Loma Linda was the first such facility to come across with the money. Of the about $40 million costs, including $20 million for a new building to house the device, approximately half was put up by the federal government, with the hospital and private donors raising the balance.

By anyone's standards, the Loma Linda device is gargantuan. Patients will never get to see the entire assembly, because walls and floors will be built around it, partly to give it human scale. The accelerator itself willl be shielded by five-to-11-foot walls intended to safeguard against radiation and other hazards, including heat and electricity.

Larger Than LifeThe contraption is definitely larger than life, its most notable feature being a trio of three-story-tall gantries resembling giant hamster runs. Each 90-ton gantry will have at its center an enclosed treatment table.

At regular intervals around each gantry are giant magnets that help direct the proton beam. Like the fine-tuning knob on an old TV set, the gantries can be rotated a little to the left or right to move the beam to any angle so that it focuses on the patient's malignancy. The machinery does the moving; the patient just lies there.

Resting within a relatively spacious capsule, 12 feet in diameter, the patient will hear soft music. He will communicate with doctors and technicians by intercom while being observed by them on a TV screen.

So he doesn't fidget out of position, the patient will be set into a customized soft-plastic body cast. The only part of the colossus he will see is the accelerator's treatment nozzle, which resembles the tip of a dental X-ray machine.

Silent Spray
The treatment itself is supposed to take anywhere from seconds to just over a minute, depending on the size and location of a tumor. The spray of protons will occur silently, so the patient won't know what hit him.

Loma Linda expects to blll cancer patients more for the new treatment than it does for conventional radiation therapy but less than it does for surgery. If the hospital were to treat cervical tumors, for example, it would price the procedure at more than $13,000 and less than $23,000.

The Food and Drug Administration has approved proton therapy as a cancer treatment, so patients treated on the Loma Linda device will qualify for reimbursement by Medicare and other insurance. Loma Linda stresses that patients won't be turned away for inability to pay.

Loma Linda is sure there will be enough patient demand for its machine. Harvard treats as many as 12 people a day running full tilt. Patients typically have a two month wait for its machine, says Herman Suit, the chairman of Harvard Medical School's department of radiation medicine. "There's no excess capacity," he says.

Questions of Fees?
The Harvard team selects patients whose tumors stand a good chance of being destroyed by beaming. At Harvard, too, there is no means test. "We've never declined anyone for financial consideration," says Dr. Suit, adding that some patients have been able to raise funds for their treatment through social and church groups.

Loma Linda says it should have the capacity to treat 100 patients a day using its three movable gantry beams and a fourth, stationary beam. "We're prepared to operate 24 hours a day if demand is high enough," says Dr. Slater.

Eventually, the hospital envisions a time when radiation therapy will be synonymous with proton therapy. Dr. Slater predicts the U.S. will have 100 machines eventually, with the cost of a machine falling to $10 million, about half what Loma Linda's prototype is costing.

A San Diego firm, Scientific Applications International Corp., has been hired by Loma Linda to market proton beam accelerators.

"The machines won't be as common as X-ray units, but really major teaching hospitals and medical centers will all have machines like this in five to 10 years," says John Glancy, a senior vice president at the company. "There will be 20 or so machines in the U.S. and a similar number in Europe."

Too Many Machines?
That prospect bothers some cancer specialists who welcome proton machines, but who wince at Mr. Glancy's numbers. They concede that proton beams already have worked wonders in certain tumors, but they say the device is unproved in most cancer cases.

The beam is virtually useless in cancers that have spread beyond the original site. Such metastacized cancers account for more than two-thirds of all malignancies says Y. Joe Kwon, a radiation oncologist in Victorville, Calif.

"There's some usefulness, no doubt about it. But the candidates for proton therapy are limited," says Dr. Kwon. "It won't make a major impact on the cure rate for all cancers. It will make a little dent, but it will cost a lot to make that dent."

Says Thomas DeLaney, a branch chief and senior Investigator at the National Cancer Institute: "The effort should be supported, but I think the number of machines necessary is small. We should have them, just like aircraft carriers, but that doesn't mean every state should have one."

Cost Effective?
Some question whether in a time of austerity, when the Bush administration proposes slashing $5 billion from the Medicare program, even one beam machine should have been constructed.

"I can't understand why the hell they built this ridiculous unit," says Joseph Imperato, a radiation oncologist and assistant professor at the Northwestern University Medical School. "It's a great physics project, but some of the medical claims are lunatic," he says.

The deeper a tumor is in the body, the fewer proven differences there are between what conventional radiation and protons can do, he says. Also, significant side effects from conventional radiation affect no more than five percent of cancer patients, he says. He fears that people suffering from cancer may draw false hope from the Loma Linda machine, a device that, so far, has few demonstrated uses.

Says Dr. Imperato: "If my administrator came to me tomorrow and asked me if he should spend $20 million to get one, I'd say to him, 'You're crazy, out of your mind. It's a waste of money'".

RADIOBIOLOGICAL RESEARCH AT THE PROTON TREATMENT CENTER

Research - an undertaking necessary to establish treatment strategies on an experimental rather than empirical basis - underlies all therapeutic uses of the proton beam. At the Proton Treatment Center, this endeavor has two major components: physics studies and radiobiological investigations. The former seek to optimally exploit the capabilities of the proton synchrotron and the beam delivery systems. The latter seek to understand the effects of proton and conventional irradiations in cells, tissues, organs and animals (including humans), particularly in relation to different dose-delivery schedules and different total radiation doses.

Figure 1

One focus of current study is the brain. A primary goal on this avenue of investigation is to identify the sequence of cell population changes that produce the tissue and organ changes, commonly known as late reactions, found months to years after a therapeutic course of irradiation has been completed. A second goal is to identify new time-dose strategies; that is, to develop proton radiation treatment schedules capable of improving cancer control while sparing normal brain tissue.

Because of its precision, the proton beam opens up a new dimension in radiobiologic studies in animals. One can confine the dose to a tightly configured volume, sparing adjacent tissue; that tissue then can be used as an effective experimental control. Pictures suggest this capability far better than words. Figure 1 shows a rat immobilized before the beam-delivery nozzle of the 100 MeV proton beam. The illuminated area corresponds to the proton-irradiated segment of the rat's brain; at the edge of the light field, the proton dose is 50 percent of maximum. Figure 2 shows a coronal section of rat brain obtained 11 months after a single proton dose of 40 Gray (4000 rad). Obvious change is seen on the left, including periventricular demyelination, necrosis and cyst formation. The right side, however, appears normal; this segment is used to compare and contrast tissue alterations observed on the irradiated side. Figure 3 shows the isodose lines from the proton beam; the 90 percent line encompasses the area of periventricular necrosis seen in figure 2.

An Innovative Application

Figure 2

When organs are irradiated, radiation biologists try to identify the kinetic changes occurring in the various tissue populations making up those organs. This task is straightforward enough in a two-dimensional laboratory dish containing tissue cultures wherein cells can be counted, but has heretofore been frustrated in the animal. As the radiation dose is increased, it is necessary to identify such changes in the three dimensions of tissue. Researchers from Loma Linda University and Loma Linda University Medical Center have begun experiments designed to yield these important measurements.

Figure 3

In collaboration with Paul McMillan, PhD, professor of anatomy at Loma Linda University, investigators in the department of radiation medicine are applying stereologic techniques to a new problem. The techniques will enable one to calculate, from biopsy specimens, the population changes in three-dimensional tissue volumes and, by extension, in organs. Although stereologic techniques are well-known in other disciplines, such as anatomy and geology, their application in radiation biology is being pioneered at Loma Linda.

With the assistance of Joseph Thompson, MD, of the section of neuroradiologoy, and Andrew Kennedy, MD, of the LLUMC house staff, radiation medicine investigators are performing histologic analyses to document and interpret changes observed on magnetic resonance images. This work seeks to determine the degree to which histologic changes can be inferred from image changes, and thus, the degree to which MRI can be employed as a measure of the brain's response to irradiation. If imaging results can be correlated precisely with histologic events, the images may be useful as monitors of therapeutic response. Thus far, the effort has enabled the investigators to identify graded changes in the brain following different total doses and different fractions of proton irradiation.

The immediate goal of this three-dimensional work is to test the hypothesis that the microvasculature is the tissue most sensitive to irradiation; that damage to the microvessels results in changes in other tissues, which in turn produce the well-known long-term sequelae. Two-dimensional measurements of the microvasculature, made on microscopic sections, do not sufficiently describe postradiation population effects; nor do they show the relationships within or between the components of tissue volumes. Using a special staining technique they developed, however, and employing computer-assisted three-dimensional reconstructions, Dr. McMillan and Marie-Helene Archambeau are evaluating the changes in brain microvessels and are comparing those changes observed with the same vessels in unirradiated brain tissue.

Other Research Areas
Researchers are measuring the dose response of V-79 (murine) cells, with the aim of characterizing proton beams of different sizes and energies. James Robertson, PhD, of East Carolina University, is conducting these studies. He has determined the dose survival of V-79 cells for the horizontal proton beam, and is now obtaining the same data for the more energetic gantry beam. These data are being compared with data from conventional radiation therapy machines, to determine the relative response of cells to similar doses from proton and photon radiations. From these data it will be possible to specify the efficiency of the protons.

In another area of concern, LLU and LLUMC investigators are measuring the different tissue and organ responses patients may have after conventional radiation treatment. The results obtained at LLU and LLUMC are compared with the same data from other clinicians, to assure that the responses are both uniform and as expected. Animal models are then employed to quantify the dose response of tissues to new time-dose schedules and to total doses of protons. The results enable researchers to evaluate what may be expected to occur in similarly irradiated normal human tissues.

New studies have been undertaken to determine the true boundary between normal brain and tumor contained within it. In collaboration with Boleslaw Liwnicz, MD, of the department of pathology, Robert Iacono, MD, of neurosurgery, and Joseph Thompson, MD, of neuroradiology, researchers from the department of radiation medicine are mapping this boundary by correlating the histologic changes seen on stereotactic biopsies, with observations detectable on magnetic resonance images.

As the work progresses, it is shared with clinicians. Researchers participate in the Pediatric Tumor Board and, when indicated, in Children's Cancer Group studies. The purpose of these contacts is to maintain a dialogue between research efforts and clinical realities, so that each may influence the other as needed. Clinicians and researchers keep each other aware of progress, as well as problems.

LLUs proton beam capability provides researchers with a new tool for many investigations. Michael Moyers, PhD, of medical physics, and Michael Kirby, PhD, of pediatrics, are applying a unique perspective in using proton beams as a tool to define tissue function. They are developing proton microbeams to study the effects of radiation-injured cells on physiologic processes. The proton beam's precision makes it feasible to irradiate critical brain centers (nuclei) of a few cells, to estimate
their role in a process such as vision.

Establishing a Foundation
Proton-beam irradiation is not experimental. Its clinical utility has been demonstrated for over forty years, and to date many more than 10,000 patients have been treated with proton beams at research facilities around the world. Loma Linda University Medical Center, however, has the potential for serving patients with disease in anatomic sites heretofore not treatable with protons, because it has the first accelerator and facility in the world designed for treating patients in a clinical setting. The facility has been designed to exploit proton beams as fully as possible, and to integrate that exploitation with clinical realities. Accordingly, the Proton Treatment Center is located adjacent to, and employs the services of, diagnosticians, researchers, and other clinicians. The research effort is part of the integrated activities expected of a referral cancer center.

This increased potential available with proton-beam therapy demands research to optimally exploit the potential. The department of radiation medicine's research program seeks to aid in this scientific effort by undertaking carefully designed and meticulously performed investigations, to apply new tools to old problems in such a way that clinical advances may build on a sound and objective basis.

HISTORY AND HERITAGE OF PROTON-BEAM THERAPY: ROBERT R. WILSON

That citation appears in many papers written by proton therapy researchers and practitioners, in acknowledgement of its pioneering nature. A small addition to the scientific literarure, it became one of the building blocks -- some would say the cornerstone -- of proton-beam radiation therapy.

Science is a cooperative venture whose lifeblood is open communications, openly conducted; it is probably inaccurate and unfair, therefore, to single out Robert Rathbun Wilson, PhD, as the founder of proton-beam therapy. Indeed, Dr. Wilson himself would disown any such identification. Speaking of Ernest O. Lawrence, Wilson (in his book, Accelerators, with Raphael Littauer, New York: Doubleday Anchor. 1960) notes that high-energy particle accelerators represent "Lawrence's dream and its fulfillment." He then says: "Such a statement is an exaggeration, of course, for the science of high-energy nuclear physics has had many roots. Even the part of it most intimately associated with Lawrence -- particle accelerators -- grew from the inspired efforts of hundreds of physicists, each with his own vision." Dr. Wilson undoubtedly views his contributions to proton-beam radiation therapy in the same light.

Still, Dr. Wilson's 1946 paper was seminal. He published it in the medical literature, to acquaint medical and biological workers with the possibilities of high-energy charged particles. He identified the characteristics of proton beams which had enormous potential for patient treatments: low skin dose; well-collinated beams; easily controllable range in tissue; and precision exposure of defined target volumes. He described how the accelerators then under construction could produce such beams. His article got the attention of radiation therapists and other physicians. Proton beams began to be used therapeutically in the mid-1950s; the Proton Treatment Center at Loma Linda is a direct descendant of the interest generated by Wilson's paper.

Robert Rathbun Wilson Hall. The sculpture in front of it, "hyperbolic obelisk,"
was designed and constructed by Dr. Wilson

Dr. Wilson's interest in the medical use of high-energy particles grew out of the neutron therapy work he witnessed at the University of California, Berkeley, where he was an undergraduate and graduate student in the 1930's. In addition, as he said in his 1946 paper, many physicists were aware that the accelerators being built after the Second World War would yield charged particles with enough energy to penetrate deeply into tissue. The implications were obvious.

Robert Wilson was born in Frontier, Wyoming, in 1914. Spending part of his growing years on a ranch, he loved the land and its creatures, and has had lifelong affection and respect for horses. He also frequented the ranch blacksmith shop, where he made things for the pure pleasure of it and, like many others who chose physics for a career, wondered how things work, and why.

That sense of wonder was whetted in 1932 when, a freshman at Berkeley, he became fascinated with the goings on in the old Radiation Laboratory on the campus. He often was late for his chemistry laboratory course because he spent so much time peering into the windows of the "Rad Lab." One day Dr. Frank Exner, a radiologist from Columbia University who was doing research at Berkeley, invited him in and showed him around, explaining the apparati and the experiments being done. Wilson was hooked. He did his undergraduate and graduate work at Berkeley, receiving his PhD in 1940.

As a graduate student, Wilson worked out the theory of the cyclotron, measured the penetration of protons into various materials, and began measuring the scattering of protons by protons. Upon graduation he became an instructor at Princeton and, with the Second World War imminent, became involved with Enrico Fermi's efforts to build a nuclear reactor. In 1943 he joined Los Alamos Laboratory, just then being formed to build the first atomic bomb. He helped organize the laboratory and brought his Princeton colleagues there to form the Cyclotron Group. He became head of the Los Alamos Research Division in 1944, with responsibility for experimental nuclear physics and, later, for the nuclear measurements which were made during the test of the bomb.

After the war, in 1945, Dr. Wilson accepted a teaching position at Harvard, where he helped design the university's cyclotron. It was during that effort that he suggested the radiological use of high-energy protons for cancer therapy. In 1947 he became Cornell University's Director of Nuclear Studies. At Cornell, he and his colleagues built a succession of electron synchrotrons, culminating in a ten-biIlion-electron-volt (10 GeV) machine in 1967. The Cornell 1.2 GeV electron synchrotron of 1953 pioneered the strong-focussing principle, and its energy made possible a new generation of nuclear studies.

At Cornell, Wilson and his colleagues made numerous discoveries. They investigated several "excited states" of the proton; they measured the production of K-mesons by an x-ray beam; they studied the scattering of electrons by protons. The latter investigations determined the shape of the proton and neutron, and confirmed the point-like structure of the electron.

In 1967, Dr. Wilson accepted the directorship of the National Accelerator Laboratory, which later was named for Enrico Fermi. He held the position through the laboratory's founding, the construction of a 500 GeV proton accelerator, and the accelerator's use in over 250 experiments, including those on the interaction of neutrinos with matter and the discovery of a new particle of the proton, the "b quark." He also worked on the design of the Fermilab Tevatron, a system of superconducting magnets which raised the energy of the proton synchrotron at Fermilab to one trillion electron volts (1000 GeV or 1 TeV). This machine was built and is still capable of producing the highest-energy particle collisions in the world, though the superconducting supercollider (SSC) will surpass it.

Dr. Wilson guided Fermilab through its first decade. He influenced not only the Laboratory's research efforts but also the physical appearance of the facility itself.

Dr. Wilson is an accomplished sculptor as well as physicist. The roots of his loves for physics and sculpture probably reside, he says, in the pleasure he experienced as a boy, making things in the ranch blacksmith shop. Building scientific artifacts gave him the same sense of satisfaction, and, while a graduate student at Berkeley, he embellished that satisfaction by going to the "Rad Lab" at night and building "big, scary figures from whatever was lying around," leaving them for people to find next day. He carved horses of wood and sculpted figures of his children. "I was always making things," he says.

Throughout his scientific career, Dr. Wilson created art as well. In 1960 he spent a sabattic year at the Academia Belli Arte in Rome, formally studying sculpture. He was commissioned to do several pieces and even considered leaving his physics profession to concentrate on his art. In 1967, however, the opportunity came to help create the National Accelerator Laboratory. As a physicist, Wilson relished the chance to create tools which would extend discoveries in the inner space of the atomic nucleus. And as an artist, Wilson saw the Illinois cornfields, which were to be the site of the laboratory, as a blank canvas.

What evolved under Dr. Wilson's influence is a collection of striking structures set within the context and contours of the land. The shapes of the Fermilab buildings suggest the work done in each. Curves are everywhere: in the buildings; on the roads; even in the pi-shaped powerline poles. The Tevatron ring, four miles in circumference, is buried in the earth, but a berm reveals its presence and encloses a tallgrass-prairie restoration. The berm is there for aesthetic reasons as well as for the functional purpose of radiation shielding; the ring could have been buried completely, but Wilson chose otherwise.

Fermilab's sixteen-story central laboratory, now named Robert Rathbun Wilson Hall, is the dominant structure on the campus. Viewed head-on, its sweeping walls and encompassed expanse of glass suggest a Gothic cathedral and it was, in fact, inspired by the cathedral at Beauvais. Like the classic cathedrals, the soaring space in the atrium is well-suited for musical performances, and many musical events are held there as well as in the adjoining Ramsey Auditorium, which was designed with acoustics in mind. Dr. Wilson played an intimate part in both buildings' design. One example of his input is the staircase in the atrium of Wilson Hall: it affords a changing vista of the countryside around and the sky above as Fermilab workers use it for moving from floor to floor and, often, for daily exercise. Outside, Wilson's "Hyperbolic Obelisk" echoes the shape of the central laboratory.

In another of the Laboratory's buildings, the proton control structure, another staircase reflects Wilson's influence. The yellow spiral recalls the DNA double helix. Radiation oncologists may find the staircase more than a little suggestive, since DNA strand breaks are one of the mechanisms whereby ionizing radiation kills cells.

Several of Dr. Wilson's sculptures are found elsewhere at the laboratory. Entering Fermilab's main driveway, one passes under "Broken Symmetry," a piece constructed from parts of a battleship and one which symbolizes what physics means for Wilson: the search for order in symmetrical relationships of knowledge, and then for deeper knowledge when that symmetry is found to be slightly broken. This piece, like most of Wilson's work, conveys a sense of rising, soaring and flowing, admixed with curves that suggest a return to the source. Even when Wilson's materials have sharp edges, the final creation evokes a smoothing -- one might say soothing -- sensation.

"Tractricious," designed by Dr. Wilson and constructed by Fermilab workers (left), is made of 16 stainless steel outer tubes from Tevatron scraps, surrounding 16 old pipes from well casings. Each tube stands alone and should withstand 80-mile-an-hour winds. "Mobius band," mounted amidst a circular pool atop Ramsey Auditorium at Fermilab (right), is built of 3"x5" pieces of stainless steel welded into a tubular form eight feet in diameter

Dr. Wilson's sculptures are found at several sites around the nation besides Fermilab. Examples reside at Princeton and Harvard, in Ithaca, New York, where he lives, and in many private collections.

In his academic life, Dr. Wilson has held a variety of appointments and has received several honors. He has been a faculty member at a number of great American universities including the University of Chicago; Princeton, Harvard and Columbia Universities; and twice at Cornell, where he now is emeritus professor of physics. In 1954 he was Exchange Professor at the University of Paris. He has been the recipient of Guggenheim and Fulbright Fellowships, and has received honorary degrees from Harvard, North Central College, Wesleyan, Notre Dame and the University of Bonn. He received the Elliot Cresson Medal in 1963, the National Medal of Science in 1973, the Fermi Award in 1984, and the Juan A. del Regato Award in 1989. He is a member of the American Physical Society and was its president in 1985. He also is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society. He helped organize and twice chaired the Federation of American Scientists.

Robert Wilson today lives in a house on the edge of a gorge in Ithaca, far above Cayugas waters. From his home Wilson can enjoy a grand vista, suitable for one who is still a Westerner at heart. He remains deeply involved in science and art, though he resists being identified as wholly a scientist or an artist. He melds the two, and includes interests in politics, philosophy and nature. As he puts it: "One tries to be a whole person, and that involves all sorts of facets - some more important than science or art."

When Dr. Wilson received the del Regato Award at Loma Linda University in 1989, he expressed pleasure at the Proton Treatment Center that was then approaching completion. It was immensely gratifying, he said, to see a particle of his life's work being put to use for the potential benefit of so many people. Recalling his days at Los Alamos during the Manhattan Project he remarked, "I never liked the idea of helping to make a bomb." That phrase recalled a scene from Surely Your Joking, Mr. Feynman, wherein the late Nobel physicist, Richard Feynman, described the day of the Trinity test at Alamogordo, New Mexico, in 1945. The first atomic bomb had been detonated, and everyone was jumping up and down with excitement that the thing had worked. Everyone but Wilson. Feynman asked him why.

"It's a terrible thing we've made," Wilson replied.

Robert Wilson felt despair that day. National emergency or no, it cut deeply against his essential grain to see such destructiveness result from his work. His whole life was, and is, attuned to creation, to understanding nature so that one might participate in its ever-creating miracle. In his own words, "Creativity is a life-affirming activity that contributes to the precious quality of life: of the individual; of the nation; of all of us."

ENDOWMENT FUNDS ESTABLISHED AT LLUMC FOR CANCER RESEARCH BY KEN VENTURI, WEBB FOUNDATION

Ken Venturi, CBS-TV golf analyst and former U.S. Open Champion, and the Del E. Webb Foundation have something in common with the Proton Treatment Center. They both recently established substantial endowment funds for proton cancer research.

Ken Venturi, professional golfer and CBS sports commentator, presents a facsimile of a
check in the amount of $275,000 to Loma Linda University Medical Center president David
B. Hinshaw, Sr., MD. Receiving the check with Dr. Hinshaw are James M. Slater, MD (left),
chair, department of radiation medicine; and B. Lyn Behrens, MB, BS, president, Loma
Linda University

Mr. Venturi has established the Loma Linda University Ken Venturi Proton Therapy Cancer Research Endowment Fund and recently turned over a check in the amount of $275,000 to help support and further new patient research projects.

As chairman and host of the annual Loma Linda University Proton Charity Invitational golf tournament, Mr. Venturi has dedicated his time and energy to "giving something back to the game and to supporting the important research that goes on at Loma Linda in the fight against cancer."

All proceeds from the proton golf tournament go to the fund that bears his name. Mr. Venturi, who has been a golf commentator for 25 years, also helps to promote the tournament nationwide as he makes his way around the country for CBS. During the proton tournament, he demonstrates his famous swing and offers tips and great humor to players at a clinic that is one of the highlights of the two-day event.

The Del E. Webb Foundation has made a grant of one million dollars to establish the Del E. Webb Cancer Research Endowment and the Del E. Webb Cancer Research Laboratory at Loma Linda University and Medical Center. The Foundation's president, R.H. Johnson, recently announced the grant by acknowledging that "the father-in-law of one of our foundation board members was treated on the proton beam and has the highest praise for the medical staff and the treatment he received. Mr. Webb, I believe, would be very pleased with the gifts we have given (more than $5 million) to Loma Linda University and Loma Linda University Medical Center."

PROTON THERAPY LIVES UP TO ITS PROMISE

The world's first and so far only hospital-based Proton Treatment Center
opened in October, 1990, at Loma Linda University Medical Center

Well into its third year of treating cancer patients, Loma Linda University Medical Center's Proton Treatment Center is fulfilling a vision of the future that medical scientists and physicists dreamed about for more than 40 years.

Skeptics said it wouldn't work. Many said it was too complicated and the machine (the first proton-beam accelerator built for hospital use), if ever built, would never run long enough to treat patients on a routine basis. Some predicted that the accelerator would be a white elephant. Others complained that its untested medical benefits and high price tag would make it the ultimate example of medical technology run amok. Some said that proton therapy would prove useless in the treatment of most cancers.

The skeptics are being proven wrong. When physicists unveiled the proton accelerator for the first time in 1989 at Fermi National Accelerator Laboratory, physicians at Loma Linda, who had been intrigued with proton cancer therapy since the early 1970's, predicted it would become a major tool in the war on cancer. Protons were first suggested as a potential cancer therapy in 1946 by Robert Wilson, who established Fermilab. Wilson's vision proved to be accurate.

The world's first and so far only hospital-based Proton Treatment Center opened in October, 1990. When the Center's first gantry came on line in 1991, it was another milestone in medical history. The gantry is a device that looks like a giant Ferris wheel as it rotates a full 360 degrees and allows physicians to direct the proton beam from virtually any angle and treat rumors anywhere in the body.
The Proton Center will reach another milestone later this summer when the second of three gantry systerns becomes operational. A third gantry will come on line this year, representing the last major hurdle in the development of a full-scale, state-of-the-art system that has the potential to replace most forms of radiation therapy and possibly render some types of surgery unnecessary.

The accelerator itself represents a major engineering accomplishment. In the past 30 months, the machine has been "down" for maintenance less than 4 days. It has been operating nearly 99 percent of the time needed to treat 35-45 patients a day.

Approximately one-half million localized cancers are treated in the U.S. each year with radiation alone or in conjunction with other forms of treatment such as surgery and chemotherapy. Now a successful new weapon, proton therapy, is finding its way into the anticancer arsenal. And, despite the fact that protons are in the early stages of clinical development, they are getting widespread attention worldwide as well as in the U.S. The success at Loma Linda, especially with treatment of tumors in the eye, brain, head and neck, lung, pancreas, bladder, and prostate, has stimulated interest for proton facilities within the scientific and medical communities of France, Switzerland, Japan, Russia, Canada, Germany, Italy, and Czechoslovakia.

X-rays (conventional radiation), are harder to control than protons. X-rays tend to scatter and damage healthy tissues to the sides of and behind a tumor. The results are unnecessary side effects. To avoid complications, physicians often lower radiation dosages to spare healthy tissue. But that can allow malignant cells to survive. Protons, on the other hand, go precisely where the physicians want them to go and no farther. So, while a tumor is being bombarded by protons, surrounding normal tissue is left intact; the patient is spared debilitating side effects.

At Loma Linda, 500 patients have been treated at the Proton Treatment Center since it opened. With two more gantries available, that number will double by the end of this year. The patients, who come from just about every state in the union and from foreign countries, are living proof that proton therapy is having an effect on the control of cancer and the relief of pain and suffering. These people represent a new hope and a new era in the possibility for an improved quality of life for cancer patients.

PROTONS PROVIDE EFFECTIVE PROSTATE TREATMENT

Prostate cancer is the most common cancer among American men and ranks second in cancer deaths. About 125,000 men will be diagnosed with prostate cancer this year, and about 35,000 will die from the disease. But this does not have to be - early detection can make a significant difference and proton therapy can effectively treat and often cure the disease.

Loma Linda University Medical Center has initiated a support group program
before, during, and after treatment for prostate cancer patients. Over a six- to
eight-week period, the group gets together for mutual help

Seeing the need for a multidisciplinary approach to treatment programs for patients with early, localized prostate cancer, Loma Linda has established a Joint Urology/Oncology Clinic as an outgrowth of increasing frustration and confusion among prostate patients who are offered conflicting treatment options for their disease.

"We saw the need to bring these disciplines together to improve the overall outlook for patients with prostate cancer," said Dr. James M. Slater, director of the Loma Linda University Cancer Institute. Recent advances at LLUMC in the use of high-precision proton-beam therapy makes it possible to treat a large number of patients and develop closer cooperation among the urologic and radiation oncologists.

Loma Linda has treated more than 250 prostate patients with proton therapy. Protons offer an effective alternative treatment to surgery and conventional radiation therapy. Because of the prostate gland's location - at the outlet of the bladder and anterior to the rectum - conventional radiation can cause side effects such as diarrhea, rectal irritation (proctitis) and/or urinary frequency or burning sensations. With protons, heavier doses and distribution can be delivered directly to the prostate.

With so many prostate patients being treated at the same time, Loma Linda has initiated a support group program before, during, and after treatment. The new program provides an opportunity for patients to discuss their feelings, reactions, treatments, and other concerns with each other and a professional facilitator.

Over a six-to eight-week period of treatment, about 30 men (some with their wives) get together weekly and help each other. Besides their positive outlook and enthusiasm for proton therapy, these men also report that weekly PSA (Prostate Specific Antigen) blood test results continue to show lower numbers (0-4 reading is considered normal). Most of the men at Loma Linda started out with unusually high PSA levels (25 or higher), but after six weeks of proton therapy, their PSA levels were reduced to near-normal single digits. This is a clear demonstration that proton treatment is effective and works without any harmful side effects.

The men in the support groups at Loma Linda are shining examples of vitality in the midst of treatment for a disease that does not have to be fatal.

NO EASY ANSWERS TO QUESTIONS ABOUT BEST CANCER TREATMENT

Just what goes into the decision-making process of surgery/radiation/chemotherapy for a cancer patient? Today's guest columnist is Arlene Lennox, Ph.D., facility head of neutron therapy at Fermi National Accelerator Laboratory in Batavia, Il., who, in a two-part series, explains some facts on the nature of cancer, the kind of information that goes into treatment-making decisions, and the different forms of radiation.

By Arlene Lennox
Guest columnist

Arlene Lennox

When diagnosed with cancer, patients will ask what treatment is best for their kind of cancer. In reality, the appropriate treatment may depend more on the stage of the disease, its location, and the patient's overall health status than on the particular type of cancer.

Generally, many early stage cancers are more easily treated by surgery, but for some, radiation therapy and/or chemotherapy may be the preferred. treatment. The same holds true for inoperable tumors, where a form of radiation therapy, sometimes combined with chemotherapy, is the best treatment.

Once the tumor has become larger and is starting to spread (metastasize) in the region of the body close to the tumor, radiation is usually recommended. Sometimes the tumor is partially removed by surgery, then radiation given to kill the remaining cancer cells.

Sometimes radiation is administered first to reduce tumor size, with the remainder removed by surgery. If there is distant metastasis in addition to a well-defined tumor, then radiation or surgery may be used to control the tumor itself. Chemotherapy is often used as well, because unlike surgery and radiation, it is able to control the spread of cancer throughout the body's entire system.

For example, there are many different varieties of lung cancer, and the appropriate treatment depends on the pathology, the biological nature of those particular lung cancer cells, as well as whether the tumor is a well-defined nodule, or diffused throughout a large volume of tissue.

Now you can see why it is impossible to give patients a simple answer to a question like, "What treatment is best for lung cancer?"

Cathedrals and accelerators represent major investments for the countries that build them. For example, Ferris noted that France in the 14th century spent a larger fraction of its wealth on cathedral construction than the USA spent in the 1960s to send astronauts to the Moon.

As major collective enterprises, a cathedral or an accelerator forms an expression of the ideals and vision of the culture that constructs it.

Cathedral or accelerator construction brings together the best talent in the land, pushing skills and technologies to their limits. Witness the development of the Gothic arch and flying buttress; or the vacuum systems that made the first Crookes tube possible, leading eventually to the Fermilab Tevatron with its superconducting magnets. Such advances enlarge the envelope of the possible!

An accelerator pushes one's thoughts outward, to model physical structures and interactions beyond the scale of our everyday experience. A cathedral lifts one's thoughts upward, to meditate upon the spiritual dimension of life and see beyond oneself. Accelerators are proud monuments to what we can know despite the finiteness of our minds. Cathedrals recall us to a spirit of humility, reminding us of greater mysteries that cannot be placed between the microscope slides of science. The accelerator and the cathedral offer complementary tools for appreciating existence: accelerators, to reduce the physical world to its fundamental parts; cathedrals, to integrate our existence holistically into a picture of purpose and meaning, Robert Wilson, the first Director of Fermilab, captured a resonance between these complementary needs in his design of the laboratory's office building, now called Wilson Hall, which was inspired by Beauvais Cathedral.[2]

There seems to be precious little public interest in physics. But the interest is very real; we simply don't know how to engage it effectively. The latent public interest presents itself on two fronts: (1) the practical curiosity to know "how things work," and (2) a deep fascination for the cosmic questions such as the origin of the universe, our place in time and space, and whether we are alone in the universe.[3] In both the practical and cosmic questions, we pass back and forth between the accelerator and the cathedral.

Daily life has been dramatically changed through the inventions of applied physics. Modern life with radio communication, networked computers, lasers, automobiles, jet planes, and non-invasive medical imaging forms a striking contrast to the grind of daily routine in medieval times.(4) Of course, the applied physics of the catapult or the hydrogen bomb also stand as reminders that the applications of the physicist's discoveries need the kind of moral guidance that one expects to be taught in cathedrals.

The design of Wilson Hall at Fermilab was modeled
on Beauvais Cathedral

Physics has shaped our knowledge of the human condition by illuminating the cosmic questions. In the matter of origins, for example, the big bang cosmology provides detailed insight into physical mechanisms, complementing the meaning questions addressed by philosophy and religion. Unfortunately, such complementarity has often and unnecessarily been seen as a conflict. A famous example arose in the trial of Galileo. That unhappy story has now reached a brighter conclusion. On November 10, 1979, Pope John Paul II commemorated the centennial of Albert Einstein's birth by proposing that the Roman Catholic Church re-examine Galileo's case. Thus in 1983, on the occasion of the 350th anniversary of the publication of Galileo's Dialogues Concerning Two World Systems, the Pope established a special Galileo Commission, stressing that through "humble and assiduous study" the Church should undertake to "dissociate the essentials of faith from the scientific system of a given age." A year later, in a formal statement the Vatican announced that "the Church had erred in condemning Galileo."(5)

One of John Paul II's biographer's notes that "Galileo's vindication after three and a half centuries was an unprecedented breakthrough in the history of the Church, but to John Paul II it represented only the first step in a much broader effort to establish a dialog between religion and modern science."(6) In a 1988 papal letter, the Pope said, "While [science and religion] can and should support each other as distinct dimensions of a common human culture, neither ought to assume that it forms a necessary premise for the other."(5) The 1984 Galileo statement, plus the ongoing publication of research by the Vatican observatory, the triennial science conferences hosted by the Pope, and his recent announcement that 'Today ... new knowledge leads to recognition of the theory of evolution as more than a hypothesis,"(7) represent serious steps to make good the attempt at dialog.(8) But large developments grow from small beginnings.

In 1953 a young Polish priest named Karol Wojtyla went on several skiing, hiking, and kayaking outings with a small group of friends. Two of the young priest's friends happened to be nuclear physicists. Although Karol Wojtyla had not been formally trained in science, one of the physicists, Jacek Hennel, recalled later that in their conversations the young priest kept trying to relate scientific topics to moral and ethical ones.(9) This was the approach Father Wojtyla would consistently apply as priest, bishop, and cardinal, and finally as Pope John Paul II, when he had to deal officially with issues of cloning and cosmology.

Not only are physicists and priests interested in the cosmic questions: so are children and parents, so are butchers, bakers, and candlestick makers. While relatively few are trained to solve differential equations or collect spectroscopic data themselves, all are interested in the larger issues that are shaped by such activities. This suggests a vision for physics which we Sigma Pi Sigma members can help implement, because we form a unique physics "alumni association."(10) The vision sees physics not only as a purveyor of technology, but, in addition, recognized as a vital liberal art, shaping community and culture. Who knows the potential within a child who asks if space ever ends, and receives a humble but knowledgeable response from someone who loves both children and physics! Who can measure the long-term benefits from the personal bridges that are built between the Jacek Hennels and the Karol Wojtylas? Each opens an important window onto the universe, and through thoughtful dialog fit their pieces of the picture together into a coherent whole!